One of the key advances in the field of renal ell cancer (RCC) is the development and approval of the tyrosine kinase inhibitors (TKIs), sorafenib and sunitinib. While these inhibitors of vascular endothelial growth factor (VEGF) driven angiogenesis have impressive clinical activity, the response to these agents is finite with resistance developing within 5-12 months. Development of resistance to such agents possibly with accompanying disease acceleration might negate much of the potential value of the therapy. We have found, in a mouse model of RCC, that resistance to sorafenib and sunitinib therapy is accompanied by a loss in interferon gamma (IFNg) signaling and that resistance occurs in the setting of renewed angiogenesis as seen by Arterial Spin Labeling Magnetic Resonance Imaging. In addition, we have found evidence that resistance to VEGFR TKI therapy is reversible as resistant tumors respond to therapy again when they are reimplanted into naive hosts. Our proposal outlines the study of the role of IFNg in resistance to VEGFR TKIs to further understand the biology of resistance. Our hypothesis is that loss of IFNg signaling is sufficient to lead to resistance and that restoration of one or more of the IFNg regulated chemokines may prevent or delay resistance to treatment with sorafenib or sunitinib. Advances in the understanding of these mechanisms of resistance could greatly enhance the therapeutic options for patients with metastatic RCC. PUBLIC HEALTH RELEVANCE: Renal cell carcinoma (RCC) exhibits a period of disease stabilization in response to inhibitors of vascular endothelial growth factor receptor (VEGFR). However, this response is inevitably ensued by the development of resistance to therapy. We have identified a loss in interferon gamma signaling at the time of resistance to VEGFR inhibitors. This proposal seeks to confirm this finding and extend it to develop new treatments for RCC.